1. Technical Field
The invention relates to the use of Aβ42 lowering agents to prevent, delay, or reverse the progression of Alzheimer's disease. The invention also relates to methods and materials involved in identifying Aβ42 lowering agents that can be used to prevent, delay, or reverse Alzheimer's disease as well as methods and materials involved in identifying agents that (1) increase the risk of developing or (2) hasten the progression of Alzheimer's disease in a mammal.
2. Background Information
Alzheimer's disease (AD) is the most common form of age-related neurodegenerative illness. The defining pathological hallmarks of AD are the presence of neurofibrillary tangles and senile plaques in the brain. Amyloid β polypeptides (Aβ) are the major constituents of amyloid plaques and are derived from altered processing of amyloid precursor proteins (APPs). Aβ consists predominantly of two forms, Aβ40 and Aβ42. Although Aβ40 is the predominant form, recent evidence suggests that Aβ42 is the pathogenic form. In addition to Aβ40 and Aβ42, the processing of APP generates other Aβ forms such as Aβ39, Aβ38, Aβ37, and Aβ34.
Genetic predisposition is the largest cause of AD in the population, accounting for perhaps 50% or more cases of this disorder (Blacker et al. (1998) Arch Neurol 55:294–6). In the past decade, epidemiological evidence suggests that non-steroidal anti-inflammatory drug (NSAID) treatment, estrogen replacement therapy, and antioxidant therapy may have beneficial effects in AD. Experimental support for these treatment methods, however, is indirect. In addition, there is no convincing evidence from randomized clinical trials that any medication tested to date slows the progression of AD. The rational development of compounds that influence key pathways or targets involved in the development of AD is critically important.